Release-sustaining agent for drugs and sustained-release pharmaceutical composition

ABSTRACT

A sustainedly releasing agent for medicines comprising a non-crosslinked type anion-exchange resin represented by the general formula (I):whereinR1 represents aralkyl or alkyl, each of R2 and R3 represents lower alkyl, R4 represents a hydrogen atom or lower alkyl, X- represents a physiologically acceptable counter ion, n represents 1-3, and p represents a mean degree of polymerization, respectively, as well as a sustainedly released medicinal composition comprising the sustainedly releasing agent and a hypolipidemic agent.

TECHNICAL FIELD

This invention relates to a sustainedly releasing agent for medicinesand a sustainedly released medicinal composition containing it. Moreparticularly, the invention relates to a sustainedly releasing agent formedicines comprising a specific non-crosslinked type anion-exchangeresin, as well as to a sustainedly released medicinal composition usefulfor the prevention or treatment of hyperlipidemia which contains thesustainedly releasing agent for medicines and a medicine having ahypolipidemic effect.

BACKGROUND ART

Hitherto, several patents have disclosed methods for binding activeingredients to ion-exchange resins. For example, active ingredients areimmobilized to cationic or anionic polystyrene-divinyl benzene resins,as described in British Patent No. 857,193. Several other patents alsodescribe methods for coating active ingredient/resin complexes. Forexample, U.S. Pat. No. 3,138,525 discloses a method for concealing thetaste of amprotopine by forming a complex with a cationic resin andcoating it with wax. Also, British Patent No. 1,218,102 describes amethod for coating with a device such as an air-fluidized bed, a complexin which a cationic active ingredient is immobilized to an anionicresin. Further, Japanese Patent Application Laid-Open Gazette No. Hei3-52824 describes a sustainedly releasing medicine capable of regulatingthe release rate of an active ingredient, which medicine comprises anactive ingredient/ion-exchange resin complex coated with an ionicpolymer having the polarity opposite to that of the resin.

DISCLOSURE OF THE INVENTION

However, where the active ingredients are anionic or liposolublemedicines, sustainedly releasing agents that exert a sufficientsustained release action have not yet been developed. Particularly, ithas been hoped that sustainedly releasing agents useful for thesustained release of medicines for the prevention or treatment ofhyperlipidemia be developed where in the past the combined use of pluralhypolipidemic medicines was difficult while sufficiently avoiding theirside effects.

This invention has been made in consideration of the problems inherentin the above-stated prior art; and it aims at providing a sustainedlyreleasing agent capable of exerting a sufficient sustained releaseaction when the active ingredient is an anionic or liposoluble medicine,which is particularly useful for the sustained release of a medicine forthe prevention or treatment of hyperlipidemia, as well as a sustainedlyreleased medicinal composition containing the agent.

As a result of extensive investigations that were repeated with the aimof accomplishing the above-mentioned object, the present inventors havediscovered the findings as described below and thus have come tocompleting the invention. Specifically, it has been discovered thatnon-crosslinked type anion-exchange resins represented by the followinggeneral formula (II):

wherein

R₁ represents benzyl group or an alkyl group of 1-20 carbons; R₂ and R₃may be the same or different, and each represents a lower alkyl group of1-4 carbons; R₄ represents a hydrogen atom or a lower alkyl group; X⁻represents a physiologically acceptable counter ion; n represents 1-3;and p represents a mean degree of polymerization of 10-10,000,respectively, as described in Japanese Patent Application Laid-OpenGazette No. Hei 8-208750 and which were developed by the presentinventors as blood cholesterol lowering agents that solves the drawbacksof bile acid adsorbents are unexpectedly useful as sustainedly releasingagents for medicines particularly where anionic or liposoluble medicinesare chosen as active ingredients, because they have hydrophobic groupswhile being non-crosslinked type anion-exchange resins; and thediscovery has led to the invention.

The sustainedly releasing agent (sustained-releasing agent) formedicines of this invention is that comprising a non-crosslinked typeanion-exchange resin (a nonbridged type anion-exchange resin)represented by the following general formula (I):

wherein

R₁ represents a moiety selected from the group consisting of aralkylgroups of 7-10 carbons and alkyl groups of 1-20 carbons; R₂ and R₃ maybe the same or different, and each represents a lower alkyl group of 1-4carbons; R₄ represents a hydrogen atom or a lower alkyl group; X⁻represents a physiologically acceptable counter ion; n represents 1-3;and p represents a mean degree of polymerization, respectively.

Further, the sustainedly released medicinal composition(sustained-releasing medicinal composition) of this invention is thatcomprising the sustainedly releasing agent that is comprised of thenon-crosslinked type anion-exchange resin represented by the generalformula (I) as described above and a medicine having a hypolipidemiceffect.

Furthermore, this invention resides in the use of the non-crosslinkedtype anion-exchange resin represented by the above-mentioned generalformula (I) as a sustainedly releasing agent for medicines.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph showing the results of Test 1 on the control of therise of blood cholesterol.

FIG. 2 is a graph showing the results of Test 2 on the control of therise of blood cholesterol.

BEST MODE FOR CARRYING OUT THE INVENTION

The sustainedly releasing agents for medicines of this inventioncomprise a non-crosslinked type anion-exchange resin represented by thegeneral formula (I) as described above. In the above-mentioned generalformula (I), substituent R₁ is an aralkyl groups of 7-10 carbons or analkyl group of 1-20 carbons, and the aryl group of the aralkyl group maycontain a substituent but is preferably nonsubstituted. In addition, thealkyl group may be a straight or branched chain type one. Among sucharalkyl groups mentioned are benzyl, phenylethyl, and the like, with thebenzyl being more preferable. Among such alkyl groups mentioned aremethyl, ethyl, n-propyl, isopropyl, hexyl, dodecyl, octadecyl, eicosyl,and the like.

Substituents R₂ and R₃ may be the same or different and are each a loweralkyl group of 1-4 carbons, which may be a straight or branched chaintype one. Among such lower alkyl groups mentioned are methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, and the like, with themethylbeing more preferable.

Substituent R₄ is a hydrogen atom or a lower alkyl group and the loweralkyl group may be a straight or branched chain type one. Among suchlower alkyl groups mentioned are methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, and the like. Such substituent R₄ is more preferablya hydrogen atom.

Although counter ion X⁻ is not particularly limited insofar as it is aphysiologically acceptable counter ion, mentioned are, for example,halide ion; anions of inorganic acid salts such as a sulfate,bicarbonate, and carbonate; and anions of organic acid salts such as aformate, acetate, propionate, malonate, succinate, fumarate, ascorbate,sulphonate, phosphate, glucuronate, and amino acid salts (e.g.,aspartate and glutamate). Among them sulfate ion, phosphate ion, andhalide ions (e.g., chloro, bromo and fluoro ions) are preferable withthe chloro ion being particularly preferable.

Furthermore, “n” that is the structural unit of the methylene group(—CH₂—) is an integer of 1-3, preferably 2. Also, “p” in the generalformula (I) as described above represents a mean degree ofpolymerization. When such mean degree of polymerization “p” is from 10to 50,000, the sustained release action against a medicine tends to begreater, which is preferable. More preferably, “p” is from 20 to 30,000,most preferably from 20 to 20,000.

Among concrete examples of such non-crosslinked type anion-exchangeresins, according to this invention, that are represented by theabove-mentioned general formula (I), mentioned are for example asfollows:

Poly(acryloyloxyethyl-N,N,N-trimethylammonium chloride);

Poly(methacryloyloxyethyl-N,N,N-trimethylammonium chloride);

Poly(acryloyloxyethyl-N,N-dimethyl-N-benzylammonium chloride);

Poly(methacryloyloxyethyl-N,N-dimethyl-N-benzylammonium chloride);

Poly(acryloyloxyethyl-N,N-dimethyl-N-hexylammonium chloride);

Poly(methacryloyloxyethyl-N,N-dimethyl-N-hexylammonium chloride);

Poly(acryloyloxyethyl-N,N-dimethyl-N-dodecylammonium chloride);

Poly(methacryloyloxyethyl-N,N-dimethyl-N-dodecyl-ammonium chloride);

Poly(acryloyloxyethyl-N,N-dimethyl-N-octylammonium chloride); and

Poly(methacryloyloxyethyl-N,N-dimethyl-N-octylammonium chloride).Poly(acryloyloxyethyl-N,N-dimethyl-N-benzyl-ammonium chloride) is morepreferable.

There are also no limitations to the method for producing anon-crosslinked type anion-exchange resin according to this invention.For example, it is possible to prepare a quaternary ammonium salt of thecorresponding monomer and to produce the resin by polymerizing this inthe presence of a polymerization initiator such as a radicalpolymerization agent.

The sustainedly releasing agent of this invention comprises anon-crosslinked type anion-exchange resin represented by the generalformula (I) as described above; and although it can be used alone or incombination with other medicines, preferably it is used in a sustainedlyreleased medicinal composition comprising the sustainedly releasingagent of this invention and a medicine. Also, it suffices that thesustainedly releasing agent as described above and the medicine arecontained in a sustainedly released medicinal composition of thisinvention; and although their forms are not particularly limited, it ispreferred that the medicine be dispersed, preferably almost in ahomogeneous manner, in the sustainedly releasing agent as describedabove.

Although such medicines are not particularly limited, medicines having ahypolipidemic effect (hereinafter sometimes referred to as“hypolipidemic agent”) may preferably be used in combination with thenon-crosslinked type anion-exchange resins according to this inventionas described above, because they have a cholesterol lowering effect oftheir own. Particularly, where the sustainedly releasing agentcomprising a non-crosslinked type anion-exchange resin represented bythe general formula (I) as described above is used in combination with amedicine for the prevention or treatment of hyperlipidemia, synergism ofthe blood cholesterol lowering effects is obtained, which is morepreferable.

For hypolipidemic agents that are used in combination with thesustainedly releasing agents comprising non-crosslinked typeanion-exchange resins of the general formula (I) as described above,preferred are those which completely differ from the bile acidadsorbents such as non-crosslinked type anion-exchange resins withrespect to the mechanism of action. Among such hypolipidemic agentsmentioned are probucol, clofibrate type medicines, nicotinic acidpreparations, squalene synthetase inhibitors, squalene epoxidaseinhibitors, hydroxymethylglutaryl coenzyme A (HMG-CoA) reductaseinhibitors, acyl coenzyme A:cholesterol acyl transferase (ACAT)inhibitors, etc.; and the HMG-CoA reductase inhibitors are morepreferable.

Particularly, the HMG-CoA reductase inhibitors have been in frequent usein recent years; and among others, they Cal lower the total serumcholesterol by about 15-20%, which makes it relatively easy to controlserum cholesterol. Among such HMG-CoA reductase inhibitors mentioned arepravastatin (U.S. Pat. Nos. 4,346,227 and 4,410,629), cerivastatin (U.S.Pat. Nos. 5,006,530 and 5,177,080), lovastatin (U.S. Pat. Nos. 4,231,938and 4,294,926), fluvastatin (U.S. Pat. Nos. 473,973 and 5,354,772),atrovastatin (U.S. Pat. No. 5,273,995), and simvastatin (U.S. Pat. No.4,450,171). Anionic medicines like pravastatin are more preferable sincethey show a more sustained action.

In addition, there are serious cases where the total serum cholesterolexceeds 300 ml/dl, and the lowering of cholesterol by any single agentscannot be satisfactory. This is evident, for example, as described inthe paper by D. R. Illingworth, “Clin. Chem. 34, No. 8, Supplement,B123-B132, 1988; entitled “Medicine Therapy for Hypercholesterolemia”:“1 Two or three kinds of medicines whose mechanisms of action aredifferent from each other can be combined for use in serioushypercholesterolemia. It is concluded that in patients suffering fromserious hypercholesterolemia, currently available medicines canadequately lower their plasma cholesterol and thus can alter theprogression of atherosclerosis at early stages.” The sustainedlyreleased medicinal compositions of this invention rely on the use of theabove-mentioned hypolipidemic agents in combination with the sustainedlyreleasing agents comprising non-crosslinked type anion-exchange resinsas described above which possess a cholesterol lowering effect of theirown in addition to a sustained release action; and therefore, they arealso useful from the standpoint of the combined use of medicines for theprevention or treatment of hyperlipidemia.

Also, in certain cases where hypolipidemic agents are combined for use,there is the possibility that they are accompanied by a side effect.This is evident, for example, from “N. Engl. J. Med., Vol. 318, No. 1, p46-47, Jan. 7, 1988,” in which D. J. Norman et al. disclose thatsarcolysis and acute kidney failure occur in heart transplantationpatients receiving the combination of lovastatin and nicotinic acid. Thesustainedly released medicinal compositions of this invention rely onthe use of the above-mentioned hypolipidemic agents in combination withthe sustainedly releasing agents comprising non-crosslinked typeanion-exchange resins as described above which possess a cholesterollowering effect of their own in addition to a sustained release action;and therefore, they are also useful for attenuating such a side effect.

In a sustainedly released medicinal composition of this invention, anon-crosslinked type anion-exchange resin having a sustained releaseaction of a medicine is combined with a medicinally effective amount ofthe medicine (preferably a hypolipidemic agent as described above) andthe composition is preferably used for oral administration.

The weight ratio of a usable hypolipidemic agent to the non-crosslinkedtype anion-exchange resin is not particularly limited, but they aredispensed where appropriate, preferably within the range of from 0.001:1to 10:1 and more preferably within the range of from 0.01:1 to 5:1.

The sustainedly released medicinal compositions of this invention exertunexpected and unique effects in the treatment of hyperlipidemia in thatthey provide an additional anticholesterolemia effect beyond thatobtained by the use of their respective active ingredients alone. Thus,even if each dose of the medicine (preferably a hypolipidemic agent) andthe non-crosslinked type anion-exchange resin as described above isreduced, their synergism accomplishes the desired pharmacologicaleffects; and further, such a side effect can also be alleviated.Moreover, the non-crosslinked type anion-exchange resins, according tothis invention, as described above have a sustained release action ofmedicines to be combined for use and provide their effects with alasting action; therefore, the desired pharmacological effects are moreefficaciously achieved over a longer period.

Although the reason that the sustainedly releasing agents comprisingnon-crosslinked type anion-exchange resins of the general formula (I) asdescribed above exert such a sustained release action is not clear, thepresent inventors interpret it as what follows. The non-crosslinked typeanion-exchange resins represented by the general formula (I) asdescribed exhibit water-absorbing ability, which is their physicalproperty; and when they absorb water, they form a gel and dissolve inwater finally. Further, they have adequate viscosity in a proper amountof water and can maintain their fluidity in the body. Owing to suchphysical properties, the object of sustainedly releasing a medicine(preferably a hypolipidemic agent) is therefore achieved unexpectedly.Namely, when the medicine and a non-crosslinked type anion-exchangeresin represented by the general formula (I) as described above (thesustainedly releasing agent of this invention) are blended to dispensetheir preparation and, for example, administered orally; the tablet formof the preparation is disintegrated in the body and the bases forsustained release in the tablets gradually absorb water in the body toform a gel; and it forms the state in which an efficacious ingredientthat is the medicine has been incorporated within. Furthermore, as itabsorbs the water in the body, the incorporation of the efficaciousingredient is lessened and the medicine is gradually released in astomach or lower alimentary canal in the body. Accordingly, thesustainedly releasing agents of this invention are believed to besufficiently effective as bases that aim at sustainedly releasing theefficacious ingredients.

When the sustainedly released medicinal compositions of this inventioncomprising the sustainedly releasing agents for medicines are to be usedfor treatment, they may be administered to mammals such as monkey, dog,cat, rat, and human. Such sustainedly released medicinal compositionscan be compounded into ordinary dosage forms for oral administrationsuch as tablets, granules, and capsules: tablets and capsules for oraladministration are more preferable. Also, when the above-mentioneddosage forms are formulated, carrier substances, excipients,disintegrators, binders, lubricants, buffers, antibacterial agents,fillers, antioxidants, and the like may be included if necessary.

Dosages for a sustainedly released medicinal composition of thisinvention should carefully be adjusted depending on the age, weight, andcondition of the subject, as well as on the route and dosage form ofadministration, daily regulations, and the desired results.Specifically, for the oral administration to obtain satisfactoryresults, where the HMG-CoA reductase inhibitor is for examplepravastatin, doses within the range of 1-100 mg may be used; and thenon-crosslinked type anion-exchange resin to be combined with thisreductase inhibitor may be used in doses within the range of 1-2,000 mg,preferably within the range of 1-500 mg. In this case it is preferredthat the HMG-CoA reductase inhibitor and the non-crosslinked typeanion-exchange resin be used in the same dosage form for oraladministration. The sustainedly released medicinal composition of thisinvention comprising the sustainedly releasing agent for medicines canbe administered in one dose or two to four divided doses per day usingthe above-mentioned dosage forms. For administration to the subject, itis advisable to start in small doses and thereafter gradually increaseto large doses.

The sustainedly released medicinal composition of this inventioncomprising the sustainedly releasing agent for medicines preferablycontains one or plural kinds of active ingredients in doses within theabove-mentioned ranges, the reminder being physiologically acceptablecarriers or other substances acceptable in standard medical practice;for example, tablets in various dimensions in a total amount of 2-2,000mg can be manufactured. The sustainedly released medicinal compositionof this invention can be made into gelatin capsules in like manner andsuch dosage forms can be administered to the subject one to four timesdaily.

When the sustainedly released medicinal compositions of this inventioncomprising the sustainedly releasing agents for medicines are to becompounded, it is possible to combine the above-mentioned activeingredients in their individual types of unit dosage forms foradministration with physiologically acceptable carriers, excipients,binders, preservatives, stabilizers, flavoring agents, and the like,according to standard medical practice. Among the concrete examples ofadjuvants that can be added to tablets, mentioned are binders such astraganth gum, arabic gum, crystalline cellulose, corn starch, andgelatin; excipients such as anhydrous calcium hydrogenphosphate,lactose, and cellulose; lubricants such as corn starch, potato starch,and magnesium alginate; sweetening agents such as sucrose, aspartame,and saccharin; and flavoring agents such as orange, peppermint,wintergreen oil and cherry. Further, when unit dosage forms foradministration are capsules, the capsules may contain liquid carrierssuch as fatty oil in addition to the above-mentioned kinds ofsubstances. Furthermore, a variety of other substances may be presenttogether to alter the physical states of the unit dosage forms foradministration, or as a coating. For example, tablets or capsules may becoated with either or both of shellac and sugar.

Further, some of the above-mentioned active ingredients form medicinallyacceptable salts generally known such as alkaline metal salts and otherordinary basic or acid addition salts. Thus, reference to fundamentalsubstances in the present specification is intended to encompassordinary salts of their compounds that can be regarded as beingsubstantially equivalent to the compounds as described.

The sustainedly released medicinal compositions of this invention may beadministered over a long period, namely four weeks to six months orlonger, as long as serum cholesterol levels are high, for example. Theycan also be used as sustainedly released medicinal compositions capableof providing prescribed doses at intervals of once or twice a week, oronce a month, and administration periods of at least one to two weeksare preferable for the purpose of obtaining minimum efficacy.

This invention will be more concretely explained on the basis ofpreferred Examples of the invention as well as Comparative Examples;however, the invention should not be limited to these examples.

Preparation of Non-crosslinked Type Anion-exchange Resins

Acryloyloxyethyl-N,N-dimethylamine (85.9 g, 0.6 mol), acetone (160 g),and hydroquinone monomethyl ether (0.1 g) as a polymerization inhibitorwere added to a double neck flask equipped with a reflux condenser anddropping funnel and mixed uniformly. Benzyl chloride (75.9 g, 0.6 mol)was added dropwise to the mixed solution obtained over about 15 min andit was allowed to stand overnight with stirring at room temperature. Theresulting reaction product was washed with 500 ml of acetone to affordcrystals of 14 E-acryloyloxyethyl-N,N-dimethylbenzylammonium chloride.

The crystals of acryloyloxyethyl-N,N-dimethyl-benzylammonium chlorideobtained (150 g) were dissolved in 280 g of purified water in a threeneck separable flask equipped with a reflux condenser and the atmospherein the flask was substituted with nitrogen for 5 h. The resultingsolution was maintained at a reaction temperature of 65° C. and to thiswas added 0.01 g of 2,2′-azobis(2-amidinopropane) hydrochloride as apolymerization initiator. After reaction for about 20 h, the resultingreaction product was precipitated in acetone to afford thenon-crosslinked type anion-exchange resin, according to this invention,represented by the following structural formula (III):

The non-crosslinked type anion-exchange resin thus obtained was used inthe following Examples and Comparative Examples.

COMPARATIVE EXAMPLE 1 ingredients weight part pravastatin 10 lactose 64microcrystalline cellulose 20 crosscarmellose sodium 2 magnesiumstearate 1 magnesium oxide 3

A pravastatin preparation in tablet forms containing the above-mentionedvarious ingredients was produced according to the procedure thatfollows. Specifically, the pravastatin, magnesium oxide, and a portionof lactose (30%) as described above were blended with a suitable mixerfor 2-10 min. The resulting mixture was passed through a #12-40 meshsize screen. Microcrystalline cellulose, crosscarmellose sodium and theremaining lactose were added to the mixture and the resulting mixturewas blended for 2-10 min. Subsequently, magnesium stearate was added tothe mixture and blending continued for 1-3 min. Further, the resultinghomogeneous mixture was subjected to tablet making to afford tabletscontaining 10 mg of pravastatin for the prevention or treatment ofhyperlipidemia.

COMPARATIVE EXAMPLE 2 ingredients weight part pravastatin 27 lactose 47microcrystalline cellulose 20 crosscarmellose sodium 2 magnesiumstearate 1 magnesium oxide 3

A pravastatin preparation in tablet forms containing the above-mentionedvarious ingredients was produced according to the procedure thatfollows. Specifically, the pravastatin, magnesium oxide, and a portionof lactose (30%) as described above were blended with a suitable mixerfor 2-10 min. The resulting mixture was passed through a #12-40 meshsize screen. Microcrystalline cellulose, crosscarmellose sodium and theremaining lactose were added to the mixture and the resulting mixturewas blended for 2-10 min. Subsequently, magnesium stearate was added tothe mixture and blending continued for 1-3 min. Further, the resultinghomogeneous mixture was subjected to tablet making to afford tabletscontaining 54 mg of pravastatin for the prevention or treatment ofhyperlipidemia.

COMPARATIVE EXAMPLE 3 ingredients weight part the non-crosslinked type89 anion-exchange resin microcrystalline cellulose 10 light silicic acidanhydride 0.5 magnesium stearate 0.5

A non-crosslinked type anion-exchange resin preparation in tablet formscontaining the above-mentioned various ingredients was producedaccording to the procedure that follows. Specifically, microcrystallinecellulose and light silicic acid anhydride were blended with a suitablemixer for 2-10 min. Next, the total amount of the non-crosslinked typeanion-exchange resin was divided into four portions and each portion wasadded to the aforementioned mixture at 5-min intervals and blended.Subsequently, magnesium stearate was taken and weighed, added to themixer and blended for 1 min. Further, the resulting homogeneous mixturewas subjected to tablet making to afford tablets containing 200 mg ofthe non-crosslinked type anion-exchange resin for the prevention ortreatment of hyperlipidemia.

COMPARATIVE EXAMPLE 4 ingredients weight part the non-crosslinked type75 anion-exchange resin microcrystalline cellulose 24 light silicic acidanhydride 0.5 magnesium stearate 0.5

A non-crosslinked type anion-exchange resin preparation in tablet formscontaining the above-mentioned various ingredients was producedaccording to the procedure that follows. Specifically, microcrystallinecellulose and light silicic acid anhydride were blended with a suitablemixer for 2-10 min. Next, the total amount of the non-crosslinked typeanion-exchange resin was divided into four portions and each portion wasadded to the aforementioned mixture at 5-min intervals and blended.Subsequently, magnesium stearate was taken and weighed, added to themixer and blended for 1 min. Further, the resulting homogeneous mixturewas subjected to tablet making to afford tablets containing 150 mg ofthe non-crosslinked type anion-exchange resin for the prevention ortreatment of hyperlipidemia.

EXAMPLE 1 ingredients weight part the non-crosslinked type 89anion-exchange resin pravastatin 0.89 microcrystalline cellulose 9.11light silicic acid anhydride 0.5 magnesium stearate 0.5

Tablets (preparation in tablet forms) containing pravastatin and thenon-crosslinked type anion-exchange resin, which contain theabove-mentioned various ingredients, were produced according to theprocedure that follows. Specifically, the pravastatin, microcrystallinecellulose and light silicic acid anhydride as described above wereblended with a suitable mixer for 2-10 min. Next, the total amount ofthe non-crosslinked type anion-exchange resin was divided into fourportions and each portion was added to the aforementioned mixture at5-min intervals and blended. Subsequently, magnesium stearate was takenand weighed, added to the mixer and blended for 1 min. Further, theresulting homogeneous mixture was subjected to tablet making to affordtablets containing 2 mg of pravastatin and 200 mg of the non-crosslinkedtype anion-exchange resin for the prevention or treatment ofhyperlipidemia.

EXAMPLE 2 ingredients weight part the non-crosslinked type 75anion-exchange resin pravastatin 6.75 microcrystalline cellulose 17.25light silicic acid anhydride 0.5 magnesium stearate 0.5

Tablets (preparation in tablet forms) containing pravastatin and thenon-crosslinked type anion-exchange resin, which contain theabove-mentioned various ingredients, were produced according to theprocedure that follows. Specifically, the pravastatin, microcrystallinecellulose and light silicic acid anhydride as described above wereblended with a suitable mixer for 2-10 min. Next, the total amount ofthe non-crosslinked type anion-exchange resin was divided into fourportions and each portion was added to the aforementioned mixture at5-min intervals and blended. Subsequently, magnesium stearate was takenand weighed, added to the mixer and blended for 1 min. Further, theresulting homogeneous mixture was subjected to tablet making to affordtablets containing 13.5 mg of pravastatin and 150 mg of thenon-crosslinked type anion-exchange resin for the prevention ortreatment of hyperlipidemia.

EXAMPLE 3 ingredients weight part the non-crosslinked type 64anion-exchange resin clofibrate 24 microcrystalline cellulose 11 lightsilicic acid anhydride 0.5 magnesium stearate 0.5

Tablets (preparation in tablet forms) containing clofibrate and thenon-crosslinked type anion-exchange resin, which contain theabove-mentioned various ingredients, were produced according to theprocedure that follows. Specifically, the clofibrate, microcrystallinecellulose and light silicic acid anhydride as described above wereblended with a suitable mixer for 2-10 min. Next, the total amount ofthe non-crosslinked type anion-exchange resin was divided into fourportions and each portion was added to the aforementioned mixture at5-min intervals and blended. Subsequently, magnesium stearate was takenand weighed, added to the mixer and blended for 1 min. Further, theresulting homogeneous mixture was subjected to tablet making to affordtablets containing 75 mg of clofibrate and 200 mg of the non-crosslinkedtype anion-exchange resin for the prevention or treatment ofhyperlipidemia.

EXAMPLE 4 ingredients weight part the non-crosslinked type 70anion-exchange resin nicomol 21 microcrystalline cellulose 8 lightsilicic acid anhydride 0.5 magnesium stearate 0.5

Tablets (preparation in tablet forms) containing nicomol and thenon-crosslinked type anion-exchange resin, which contain theabove-mentioned various ingredients, were produced according to theprocedure that follows. Specifically, the nicomol, microcrystallinecellulose and light silicic acid anhydride as described above wereblended with a suitable mixer for 2-10 min. Next, the total amount ofthe non-crosslinked type anion-exchange resin was divided into fourportions and each portion was added to the aforementioned mixture at5-min intervals and blended. Subsequently, magnesium stearate was takenand weighed, added to the mixer and blended for 1 min. Further, theresulting homogeneous mixture was subjected to tablet making to affordtablets containing 60 mg of nicomol and 200 mg of the non-crosslinkedtype anion-exchange resin for the prevention or treatment ofhyperlipidemia.

TESTING EXAMPLE 1

(In Vitro Elution Test of Pravastatin Tablets and Tablets ContainingPravastatin and the Non-crosslinked Type Anion-exchange Resin)

The pravastatin tablets prepared in Comparative Example 1 and thetablets containing pravastatin and the non-crosslinked typeanion-exchange resin prepared in Example 1 were used to conduct theelution test of pravastatin according to “1 Elution Test Methods (Paddlemethod)” in the Pharmacopoeia of Japan. In addition, the agitation speedin the test was set to 50 rpm. The results obtained are shown in Table 1as described below.

TABLE 1 time to tablet containing reach the pravastatin and the elutionpravastatin non-crosslinked type percentage (Comparative anion-exchangeresin elution solution (*1) Example 1) (Example 1) pH1.2 solution T75%6.1 (min)  197.0 (min) (1st solution: T95% 7.9 (min)  237.1 (min) ThePharmacopoeia) pH4.0 solution T75% 4.3 (min) 165.35 (min) 0.1M (1stsolution: T95% 5.6 (min)  209.2 (min) The Pharmacopoeia) pH6.8 solutionT75% 7.0 (min)  165.1 (min) (2nd solution: T95% 9.8 (min)  210.4 (min)The Pharmacopoeia) (*1) Times for the elution percentage of pravastatinto reach 75% and 95% were determined, respectively; and the time toreach 75% was designated “T75%” and the time to reach 95%, “T95%”.

From the results shown in Table 1, it was apparent that where thetablets containing pravastatin and the non-crosslinked typeanion-exchange resin were used (Example 1), the elution of pravastatinwas slow as compared to the case where the pravastatin tablets were usedalone (Comparative Example 1). In other words, it was ascertained thatthe non-crosslinked type anion-exchange resins according to thisinvention sustainedly release pravastatin and the efficacy ofpravastatin is more sustainedly manifested.

TESTING EXAMPLE 2

(Test 1 on the Control of the Rise of Blood Cholesterol in NZW MaleRabbits Fed Cholesterol Load)

Employing NZW rabbits fed cholesterol load, experiments on thecontrolling effect on the rise of blood cholesterol were performed asdescribed below in the following cases: where the 10 mg pravastatintablets prepared in Comparative Example 1 (1 tablet per day) were used;where the 200 mg non-crosslinked type anion-exchange resin tabletsprepared in Comparative Example 3 (5 tablets per day) were used; wherethe tablets containing 2 mg of pravastatin and 200 mg of thenon-crosslinked type anion-exchange resin prepared in Example 1 (5tablets per day) were used; and where the 10 mg pravastatin tabletsprepared in Comparative Example 1 (1 tablet per day) and the 200 mgnon-cross linked type anion-exchange resin tablets prepared inComparative Example 3 (5 tablets per day) were used together.

Specifically, the NZW male rabbits were fed chow containing 0.67%cholesterol for 21 days. On the 7th day after the start of cholesterolloading, the NZW male rabbits were divided into groups so that the totalserum cholesterol level in each group was almost equal. From the 8th dayafter the start of cholesterol loading, oral administration of each ofthe above-mentioned medicinal compositions continued for 14 days. On theday when the medicine administration started and the 14th daythereafter, blood was collected to measure the total serum cholesterollevels for comparison. The results obtained are shown in FIG. 1.

From the results shown in FIG. 1, it was apparent that where the tabletscontaining 2 mg of pravastatin and 200 mg of the non-crosslinked typeanion-exchange resin (5 tablets per day) were used (Example 1), therewere no significant differences in the controlling effect of the rise ofblood cholesterol when compared to the case where only the 200 mgnon-crosslinked type anion-exchange resin tablets (5 tablets per day)were used (Comparative Example 3), or the case where the 10 mgpravastatin tablets (1 tablet per day) and the 200 mg non-crosslinkedtype anion-exchange resin tablets (5 tablets per day) were used together(Comparative Example 1 plus Comparative Example 3). On the other hand,where the tablets containing 2 mg of pravastatin and 200 mg of thenon-crosslinked type anion-exchange resin (5 tablets per day) were used(Example 1), the controlling effect of the rise of blood cholesterol wasgreater than the case where only the 10 mg pravastatin tablets (1 tabletper day) were used (Comparative Example 1). Accordingly, it wasascertained that the tablets according to this invention containingpravastatin and the non-crosslinked type anion-exchange resin are ableto markedly control the rise of blood cholesterol as compared to thepravastatin tablets only, and are very effective in the treatment ofhyperlipidemia.

TESTING EXAMPLE 3

(Test 2 on Control of the Rise of Blood Cholesterol in NZW Male RabbitsFed Cholesterol Load)

Employing NZW rabbits fed cholesterol load, experiments on thecontrolling effect on the rise of blood cholesterol were performed asdescribed below in the following cases: where the 54 mg pravastatintablets prepared in Comparative Example 2 (1 tablet per day) were used;where the 150 mg non-crosslinked type anion-exchange resin tabletsprepared in Comparative Example 4 (4 tablets per day) were used; wherethe tablets containing 13.5 mg of pravastatin and 150 mg of thenon-crosslinked type anion-exchange resin prepared in Example 2 (4tablets per day) were used; and where the 54 mg pravastatin tabletsprepared in Comparative Example 2 (1 tablet per day) and the 150 mgnon-cross linked type anion-exchange resin tablets prepared inComparative Example 4 (4 tablets per day) were used together.

Specifically, the NZW male rabbits were fed chow containing 0.67%cholesterol for 21 days. On the 7th day after the start of cholesterolloading, the NZW male rabbits were divided into groups so that the totalserum cholesterol level in each group was almost equal. From the 8th dayafter the start of cholesterol loading, oral administration of each ofthe above-mentioned medicinal compositions continued for 14 days. On theday when the medicine administration started and the 14th daythereafter, blood was collected to measure the total serum cholesterollevels for comparison. The results obtained are shown in FIG. 2.

From the results shown in FIG. 2, it was apparent that where the tabletscontaining 13.5 mg of pravastatin and 150 mg of the non-crosslinked typeanion-exchange resin (4 tablets per day) were used (Example 2), thereexhibited a significant controlling effect of the rise of bloodcholesterol when compared to the case where only the 54 mg pravastatintablets (1 tablets per day) were used (Comparative Example 2) and thecase where only the 150 mg non-crosslinked type anion-exchange resintablets (4 tablets per day) were used (Comparative Example 4).Furthermore, where the tablets containing 13.5 mg of pravastatin and 150mg of the non-crosslinked type anion-exchange resin (4 tablets per day)were used (Example 2), the controlling effect of the rise of bloodcholesterol was greater even than the case where the 54 mg pravastatintablets (1 tablet per day) and the 150 mg non-crosslinked typeanion-exchange resin tablets (4 tablets per day) were used together(Comparative Example 2 plus Comparative Example 4). Accordingly, it wasascertained that the tablets according to this invention containingpravastatin and the non-crosslinked type anion-exchange resin are ableto markedly control the rise of blood cholesterol as compared with theuse of pravastatin tablets alone, the use of non-crosslinked typeanion-exchange resin tablets alone, or the combined use of pravastatintablets and non-crosslinked type anion-exchange resin tablets, and arevery effective in the treatment of hyperlipidemia.

TEST EXAMPLE 4

(Measurement of the Variation of Blood Concentrations of Pravastatin inNZW Male Rabbits)

A 54 mg pravastatin tablet (I tablet) prepared in Comparative Example 2and tablets (4 tablets) prepared in Example 2 containing 13.5 mg ofpravastatin and 150 mg of the non-crosslinked type anion-exchange resinwere orally administered to NZW male rabbits at a single time,respectively. Plasma concentrations of pravastatin were measured to findAUC (ng/ml·h) and T_(max) (h).

As a result, AUC showed almost no variation and T_(max) increased in thecase where the tablet containing pravastatin and the non-crosslinkedtype anion-exchange resin was used, as compared with the case where thepravastatin tablet alone was used. Accordingly, it was ascertained thatin a tablet containing pravastatin and the non-crosslinked typeanion-exchange resin, the non-crosslinked type anion-exchange resinsustainedly releases pravastatin and the efficacy of pravastatin is moresustainedly manifested.

INDUSTRIAL APPLICABILITY

The non-crosslinked type anion-exchange resins according to thisinvention possess hydrophobic groups while being non-crosslinkedanion-exchange resins; therefore, the sustainedly releasing agents ofthe invention comprising the non-crosslinked type anion-exchange resinsas described above have enabled the sustained release of such medicinesover a longer period with more steadiness even where anionic orliposoluble medicines are particularly chosen as active ingredients.

Further, the non-crosslinked type anion-exchange resins according tothis invention possess a controlling effect on the rise of cholesterolof their own in addition to the sustained release effect as describedabove; therefore, the sustainedly released medicinal compositions of theinvention in which the sustainedly releasing agents comprising thenon-crosslinked anion-exchange resins and hypolipidemic agents arecombined for use have produced synergism of the blood cholesterollowering effects by both ingredients as described above, and at the sametime have enabled the sustained action of the hypolipidemic agents overa long period with more steadiness.

What is claimed is:
 1. A sustainedly released medicinal compositioncomprising a sustainedly releasing agent for medicines and a medicinehaving a hypolipidemic effect, said sustainedly releasing agentcomprising a non-crosslinked type anion-exchange resin represented bythe following general formula (I):

wherein R¹ represents a moiety selected from the group consisting ofaralkyl groups of 7-10 carbons and alkyl groups of 1-20 carbons; R² andR³ may be the same or different and each represents a hydrogen atom or alower alkyl group; x⁻ represents a physiologically acceptable counterion; n represents 1-3; and p represents a mean degree of polymerization,respectively; and said medicine having a hypolipidemic effect is atleast one medicine selected from the group consisting of probucol, aclofibrate-containing medicine, a nicotininc acid-containing medicine, asqualene synthetase inhibitor, a squalene epoxidase inhibitor, ahydroxymethylglutaryl coenzyme A reductase inhibitor, and an acylcoenzyme A: cholesterol acyl transferase inhibitor.
 2. The sustainedlyreleased medicinal composition according to claim 1, wherein R₁ isbenzyl, R₂ is methyl, R₃ is methyl, R₄ is a hydrogen atom, X⁻ is achlorine ion, and n is
 2. 3. The sustainedly released medicinalcomposition according to claim 1, wherein the weight ratio of themedicine having a hypolipidemic effect to the non-crosslinkedanion-exchange resin is within the range of from 0.001:1 to 10:1.
 4. Thesustainedly released medicinal composition according to claim 1, whereinthe medicine having a hypolipidemic effect is dispersed in thenon-crosslinked anion-exchange resin.
 5. The sustainedly releasedmedicinal composition according to claim 1, wherein p represents a meandegree of polymerization of 20 to 20,000.